Blood processing systems and methods using apparent hematocrit as a process control parameter

ABSTRACT

Blood processing systems and methods separate whole blood into red blood cells and a plasma constituent within a rotating centrifugal separation device. The systems and methods convey whole blood into the separation device through an inlet path including a pump operable at a prescribed rate. The systems and methods remove plasma constituent from the separation device through an outlet path including a pump operable at a prescribed rate. The systems and methods derive a value H b  representing an apparent hematocrit of whole blood entering the separation device, where:          H   b     =         H   rbc          (       Q   b     -     Q   p       )         Q   b                       
     and where H rbc  is a value relating to hematocrit of red blood cells in the separation device. The systems and methods generate outputs and control commands based, at least in part, upon H b .

This application is a continuation of application Ser. No. 08/960,674filed Oct. 30, 1997, now U.S. Pat. No. 6,059,979, which is acontinuation of application Ser. No. 08/473,316 filed Jun. 7, 1995, nowU.S. Pat. No. 5,730,883, which is a continuation-in-part of applicationSer. No. 08/097,967, filed on Jul. 26, 1993, now abandoned, which is acontinuation-in-part of U.S. application Ser. No. 07/965,088, filed onOct. 22, 1992, now U.S. Pat. No. 5,370,802, which is acontinuation-in-part of U.S. application Ser. No. 07/814,403, filed onDec. 23, 1991, now abandoned.

FIELD OF THE INVENTION

The invention generally relates to blood processing systems and methods.

BACKGROUND OF THE INVENTION

Today people routinely separate whole blood by centrifugation into itsvarious therapeutic components, such as red blood cells, platelets, andplasma.

Certain therapies transfuse large volumes of blood components. Forexample, some patients undergoing chemotherapy require the transfusionof large numbers of platelets on a routine basis. Manual blood bagsystems simply are not an efficient way to collect these large numbersof platelets from individual donors.

On line blood separation systems are today used to collect large numbersof platelets to meet this demand. On line systems perform the separationsteps necessary to separate concentration of platelets from whole bloodin a sequential process with the donor present. On line systemsestablish a flow of whole blood from the donor, separate out the desiredplatelets from the flow, and return the remaining red blood cells andplasma to the donor, all in a sequential flow loop.

Large volumes of whole blood (for example, 2.0 liters) can be processedusing an on line system. Due to the large processing volumes, largeyields of concentrated platelets (for example, 4×10¹¹ plateletssuspended in 200 ml of fluid) can be collected. Moreover, since thedonor's red blood cells are returned, the donor can donate whole bloodfor on line processing much more frequently than donors for processingin multiple blood bag systems.

Nevertheless, a need still exists for further improved systems andmethods for collecting cellular-rich concentrates from blood componentsin a way that lends itself to use in high volume, on line bloodcollection environments, where higher yields of critically neededcellular blood components like platelets can be realized.

As the operational and performance demands upon such fluid processingsystems become more complex and sophisticated, the need exists forautomated process controllers that can gather and generate more detailedinformation and control signals to aid the operator in maximizingprocessing and separation efficiencies.

SUMMARY OF THE INVENTION

The invention provides blood processing systems and methods thatseparate whole blood into red blood cells and a plasma constituentwithin a rotating centrifugal separation device. The systems and methodsconvey whole blood into the separation device through an inlet pathincluding a pump operable at a prescribed rate. The systems and methodsremove plasma constituent from the separation device through an outletpath including a pump operable at a prescribed rate.

According to the invention, the systems and methods derive a value H_(b)representing an apparent hematocrit of whole blood entering theseparation device, where:$H_{b} = \frac{H_{rbc}\left( {Q_{b} - Q_{p}} \right)}{Q_{b}}$

and where H_(rbc) is a value relating to hematocrit of red blood cellsin the separation device.

In a preferred embodiment, the systems and methods generate a controlcommand based, at least in part, upon H_(b). In one implementation, thecontrol command recirculates at least a portion of plasma constituentfor mixing with whole blood conveyed into the separation device. Inanother implementation, the control command controls Q_(b).

In a preferred embodiment, the systems and methods generate an outputbased, at least in part, upon H_(b). In one implementation, the outputcomprises a value η representing efficiency of separation in theseparation device, where:$\eta = \frac{Q_{p}}{\left( {1 - H_{b}} \right)Q_{b}}$

In a preferred embodiment, the value H_(rbc) represents apparenthematocrit of red blood cells in the separation device, where:$H_{rbc} = {1 - \left( {\frac{\beta}{g\quad A\quad \kappa \quad S_{\mathrm{\Upsilon}}}\left( {q_{b} - q_{p}} \right)} \right)^{\frac{1}{k + 1}}}$

where:

q_(b) is inlet blood flow rate (cm³/sec), which when converted toml/min, corresponds with Q_(b),

q_(p) is measured plasma flow rate (in cm³/sec), which, when convertedto ml/min corresponds with Q_(p),

β is a shear rate dependent term, and S_(Y) is a red blood cellsedimentation coefficient (sec) and β/S_(Y)=15.8×10⁶ sec⁻¹,

A is the area of the separation device (cm²),

g is the centrifugal acceleration (cm/sec²), which is the radius of theseparation device multiplied by the rate of rotation squared Ω²(rad/sec²), and

k is a viscosity constant=0.625, and K is a viscosity constant basedupon k and another viscosity constant α=4.5, where:$\kappa = {{\frac{k + 2}{\alpha}\left\lbrack \frac{k + 2}{k + 1} \right\rbrack}^{k + 1} = 1.272}$

In a preferred embodiment, the systems and methods operate free of any asensor to measure blood hematocrit either in the separation device or inthe inlet path.

In a preferred embodiment, the systems and methods recirculate at leasta portion of plasma constituent from the separation device at aprescribed rate Q_(Recirc) for mixing with whole blood conveyed into theseparation device. In this embodiment, the systems and methods controlQ_(Recirc) to achieve a desired hematocrit H_(i) for whole bloodconveyed into the separation device as follows:$Q_{Recirc} = {\left\lbrack {\frac{H_{b}}{H_{i}} - 1} \right\rbrack \times Q_{b}}$

The various aspects of the invention are especially well suited for online blood separation processes.

Other features and advantages of the invention will become apparent fromthe following description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic view of a dual needle platelet collectionsystem that includes a controller that embodies the features of theinvention;

FIG. 2 is a diagrammatic flow chart view of the controller andassociated system optimization application that embodies the features ofthe invention;

FIG. 3 is a diagrammatic view of the function utilities contained withinthe system optimization application shown in FIG. 2;

FIG. 4 is a diagrammatic flow chart view of the utility functioncontained within the system optimization application that derives theyield of platelets during a given processing session;

FIG. 5 is a diagrammatic flow chart view of the utility functionscontained within the system optimization application that provideprocessing status and parameter information, generate control variablesfor achieving optimal separation efficiencies, and generate controlvariables that control the rate of citrate infusion during a givenprocessing session;

FIG. 6 is a diagrammatic flow chart view of the utility functioncontained within the system optimization application that recommendsoptimal storage parameters based upon the yield of platelets during agiven processing session;

FIG. 7 is a diagrammatic flow chart view of the utility functioncontained within the system optimization application that estimates theprocessing time before commencing a given processing session;

FIG. 8 is a graphical depiction of an algorithm used by the utilityfunction shown in FIG. 4 expressing the relationship between theefficiency of platelet separation in the second stage chamber and adimensionless parameter, which takes into account the size of theplatelets, the plasma flow rate, the area of the chamber, and the speedof rotation;

FIG. 9 is a graph showing the relationship between the partial pressureof oxygen and the permeation of a particular storage container, whichthe utility function shown in FIG. 6 takes into account in recommendingoptimal storage parameters in terms of the number of storage containers;

FIG. 10 is a graph showing the relationship between the consumption ofbicarbonate and storage thrombocytocrit for a particular storagecontainer, which the utility function shown in FIG. 6 takes into accountin recommending optimal storage parameters I n terms of the volume ofplasma storage medium; and

FIG. 11 is a graph showing the efficiency of platelet separation,expressed in terms of mean platelet volume, in terms of inlethematocrit, which a utility function shown in FIG. 5 takes into accountin generating a control variable governing plasma recirculation duringprocessing.

The various aspects of the invention may be embodied in several formswithout departing from its spirit or essential characteristics. Thescope of the invention is defined in the appended claims, rather than inthe specific description preceding them. All embodiments that fallwithin the meaning and range of equivalency of the claims are thereforeintended to be embraced by the claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 shows in diagrammatic form an on line blood processing system 10for carrying out an automated platelet collection procedure. The system10 in many respects typifies a conventional two needle blood collectionnetwork, although a convention single needle network could also be used.The system 10 includes a processing controller 18 embodying the featuresof the invention.

I. The Separation system

The system 10 includes an arrangement of durable hardware elements,whose operation is governed by the processing controller 18. Thehardware elements include a centrifuge 12, in which whole blood (WB) isseparated into its various therapeutic components, like platelets,plasma, and red blood cells (RBC). The hardware elements will alsoinclude various pumps, which are typically peristaltic (designated P1 toP4); and various in line clamps and valves (designated V1 to V3). Ofcourse, other types of hardware elements may typically be present, whichFIG. 1 does not show, like solenoids, pressure monitors, and the like.

The system 10 typically also includes some form of a disposable fluidprocessing assembly 14 used in association with the hardware elements.

In the illustrated blood processing system 10, the assembly 14 includesa two stage processing chamber 16. In use, the centrifuge 12 rotates theprocessing chamber 16 to centrifugally separate blood components. Arepresentative centrifuge that can be used is shown in Williamson et alU.S. Pat. No. 5,360,542, which is incorporated herein by reference.

The construction of the two stage processing chamber 16 can vary. Forexample, it can take the form of double bags, like the processingchambers shown in Cullis et al. U.S. Pat. No. 4,146,172. Alternatively,the processing chamber 16 can take the form of an elongated two stageintegral bag, like that shown in Brown U.S. Pat. No. 5,370,802.

In the illustrated blood processing system 10, the processing assembly14 also includes an array of flexible tubing that forms a fluid circuit.The fluid circuit conveys liquids to and from the processing chamber 16.The pumps P1-P4 and the valves V1-V3 engage the tubing to govern thefluid flow in prescribed ways. The fluid circuit further includes anumber of containers (designated C1 to C3) to dispense and receiveliquids during processing.

The controller 18 governs the operation of the various hardware elementsto carry out one or more processing tasks using the assembly 14. Thecontroller 18 also performs real time evaluation of processingconditions and outputs information to aid the operator in maximizing theseparation and collection of blood components. The inventionspecifically concerns important attributes of the controller 18.

The system 10 can be configured to accomplish diverse types of bloodseparation processes. FIG. 1 shows the system 10 configured to carry outan automated two needle platelet collection procedure.

In a collection mode, a first tubing branch 20 and the whole blood inletpump P2 direct WB from a draw needle 22 into the first stage 24 of theprocessing chamber 16. Meanwhile, an auxiliary tubing branch 26 metersanticoagulant from the container C1 to the WB flow through theanticoagulant pump P1. While the type of anticoagulant can vary, theillustrated embodiment uses ACDA, which is a commonly used anticoagulantfor pheresis.

The container C2 holds saline solution. Another auxiliary tubing branch28 conveys the saline into the first tubing branch 20, via the in linevalve V1, for use in priming and purging air from the system 10 beforeprocessing begins. Saline solution is also introduced again afterprocessing ends to flush residual components from the assembly 14 forreturn to the donor.

Anticoagulated WB enters and fills the first stage 24 of the processingchamber 24. There, centrifugal forces generated during rotation of thecentrifuge 12 separate WB into red blood cells (RBC) and platelet-richplasma (PRP).

The PRP pump P4 operates to draw PRP from the first stage 24 of theprocessing chamber 16 into a second tubing branch 30 for transport tothe second stage 32 of the processing chamber 16. There, the PRP isseparated into platelet concentrate (PC) and platelet-poor plasma (PPP).

Optionally, the PRP can be conveyed through a filter F to removeleukocytes before separation in the second stage 32. The filter F canemploy filter media containing fibers of the type disclosed in Nishimuraet al U.S. Pat. No. 4,936,998, which is incorporated herein byreference. Filter media containing these fibers are commercially sold byAsahi Medical Company in filters under the trade name SEPACELL.

The system 10 includes a recirculation tubing branch 34 and anassociated recirculation pump P3. The processing controller 18 operatesthe pump P3 to divert a portion of the PRP exiting the first stage 24 ofthe processing chamber 16 for remixing with the WB entering the firststage 24 of the processing chamber 16. The recirculation of PRPestablishes desired conditions in the entry region of the first stage 24to provide maximal separation of RBC and PRP.

As WB is drawn into the first chamber stage 24 for separation, theillustrated two needle system simultaneously returns RBC from the firstchamber stage 24, along with a portion of the PPP from the secondchamber stage 32, to the donor through a return needle 36 through tubingbranches 38 and 40 and in line valve V2.

The system 10 also collects PC (resuspended in a volume of PPP) in someof the containers C3 through tubing branches 38 and 42 and in line valveV3 for storage and beneficial use. Preferable, the container(s) C3intended to store the PC are made of materials that, when compared toDEHP-plasticized polyvinyl chloride materials, have greater gaspermeability that is beneficial for platelet storage. For example,polyolefin material (as disclosed in Gajewski et al U.S. Pat. No.4,140,162), or a polyvinyl chloride material plasticized withtri-2-ethylhexyl trimellitate (TEHTM) can be used.

The system 10 can also collect PPP in some of the containers C3 throughthe same fluid path. The continuous retention of PPP serves multiplepurposes, both during and after the component separation process.

The retention of PPP serves a therapeutic purpose during processing. PPPcontains most of the anticoagulant that is metered into WB during thecomponent separation process. By retaining a portion of PPP instead ofreturning it all to the donor, the overall volume of anticoagulantreceived by the donor during processing is reduced. This reduction isparticularly significant when large blood volumes are processed. Theretention of PPP during processing also keeps the donor's circulatingplatelet count higher and more uniform during processing.

The system 10 can also derive processing benefits from the retained PPP.

The system 10 can, in an alternative recirculation mode, recirculate aportion of the retained PPP, instead of PRP, for mixing with WB enteringthe first compartment 24. Or, should WB flow be temporarily haltedduring processing, the system 10 can draw upon the retained volume ofPPP as an anticoagulated “keep-open” fluid to keep fluid lines patent.In addition, at the end of the separation process, the system 10 drawsupon the retained volume of PPP as a “rinse-back” fluid, to resuspendand purge RBC from the first stage compartment 24 for return to thedonor through the return branch 40. After the separation process, thesystem 10 also operates in a resuspension mode to draw upon a portion ofthe retained PPP to resuspend PC in the second compartment 24 fortransfer and storage in the collection container(s) C3.

II. The System Controller

The controller 18 carries out the overall process control and monitoringfunctions for the system 10 as just described.

In the illustrated and preferred embodiment (see FIG. 2), the controllercomprises a main processing unit (MPU) 44. In the preferred embodiment,the MPU 44 comprises a type 68030 microprocessor made by MotorolaCorporation, although other types of conventional microprocessors can beused.

In the preferred embodiment, the MPU 44 employs conventional real timemulti-tasking to allocate MPU cycles to processing tasks. A periodictimer interrupt (for example, every 5 milliseconds) preempts theexecuting task and schedules another that is in a ready state forexecution. If a reschedule is requested, the highest priority task inthe ready state is scheduled. Otherwise, the next task on the list inthe ready state is schedule.

A. Functional Hardware Control

The MPU 44 includes an application control manager 46. The applicationcontrol manager 46 administers the activation of a library 48 of controlapplications (designated A1 to A3). Each control application A1-A3prescribes procedures for carrying out given functional tasks using thesystem hardware (e.g., the centrifuge 12, the pumps P1-P4, and thevalves V1-V3) in a predetermined way. In the illustrated and preferredembodiment, the applications A1-A3 reside as process software in EPROM'sin the MPU 44.

The number of applications A1-A3 can vary. In the illustrated andpreferred embodiment, the library 48 includes at least one clinicalprocedure application A1. The procedure application A1 contains thesteps to carry out one prescribed clinical processing procedure. For thesake of example in the illustrated embodiment, the library 48 includes aprocedure application A1 for carrying out the dual needle plateletcollection process, as already generally described in connection withFIG. 1. Of course, additional procedure applications can be, andtypically will be, included. For example, the library 48 can include aprocedure application for carrying out a conventional single needleplatelet collection process.

In the illustrated and preferred embodiment, the library 48 alsoincludes a system optimization application A2. The system optimizationapplication A2 contains interrelated, specialized utility functions thatprocess information based upon real time processing conditions andempirical estimations to derive information and control variables thatoptimize system performance. Further details of the optimizationapplication A2 will be described later.

The library 48 also includes a main menu application A3, whichcoordinates the selection of the various applications A1-A3 by theoperator, as will also be described in greater detail later.

Of course, additional non-clinical procedure applications can be, andtypically will be, included. For example, the library 48 can include aconfiguration application, which contains the procedures for allowingthe operator to configure the default operating parameters of the system10. As a further example, the library 48 can include a diagnosticapplication, which contains the procedures aiding service personnel indiagnosing and troubleshooting the functional integrity of the system,and a system restart application, which performs a full restart of thesystem, should the system become unable to manage or recover from anerror condition.

An instrument manager 50 also resides as process software in EPROM's inthe MPU 44. The instrument manager 50 communicates with the applicationcontrol manager 46. The instrument manager 50 also communicates with lowlevel peripheral controllers 52 for the pumps, solenoids, valves, andother functional hardware of the system.

As FIG. 2 shows, the application control manager 46 sends specifiedfunction commands to the instrument manager 50, as called up by theactivated application A1-A3. The instrument manager 50 identifies theperipheral controller or controllers 52 for performing the function andcompiles hardware-specific commands. The peripheral controllers 52communicate directly with the hardware to implement thehardware-specific commands, causing the hardware to operate in aspecified way. A communication manager 54 manages low-level protocol andcommunications between the instrument manager 50 and the peripheralcontrollers 52.

As FIG. 2 also shows, the instrument manager 50 also conveys back to theapplication control manager 46 status data about the operational andfunctional conditions of the processing procedure. The status data isexpressed in terms of, for example, fluid flow rates, sensed pressures,and fluid volumes measured.

The application control manager 46 transmits selected status data fordisplay to the operator. The application control manager 46 transmitsoperational and functional conditions to the procedure application A1and the performance monitoring application A2.

B. User Interface Control

In the illustrated embodiment, the MPU 44 also includes an interactiveuser interface 58. The interface 58 allows the operator to view andcomprehend information regarding the operation of the system 10. Theinterface 58 also allows the operator to select applications residing inthe application control manager 46, as well as to change certainfunctions and performance criteria of the system 10.

The interface 58 includes an interface screen 60 and, preferably, anaudio device 62. The interface screen 60 displays information forviewing by the operator in alpha-numeric format and as graphical images.The audio device 62 provides audible prompts either to gain theoperator's attention or to acknowledge operator actions.

In the illustrated and preferred embodiment, the interface screen 60also serves as an input device. It receives input from the operator byconventional touch activation. Alternatively or in combination withtouch activation, a mouse or keyboard could be used as input devices.

An interface controller 64 communicates with the interface screen 60 andaudio device 62. The interface controller 64, in turn, communicates withan interface manager 66, which in turn communicates with the applicationcontrol manager 46. The interface controller 64 and the interfacemanager 66 reside as process software in EPROM's in the MPU 44.

Further details of the interface 58 are disclosed in copendingapplication Serial No. xxx.

C. The System Optimization Application

In the illustrated embodiment (as FIG. 3 shows), the system optimizationapplication A2 contains six specialized yet interrelated utilityfunctions, designated F1 to F6. Of course, the number and type ofutility functions can vary.

In the illustrated embodiment, a utility function F1 derives the yieldof the system 10 for the particular cellular component targeted forcollection. For the platelet collection procedure application Al, theutility function F1 ascertains both the instantaneous physical conditionof the system 10 in terms of its separation efficiencies and theinstantaneous physiological condition of the donor in terms of thenumber of circulating platelets available for collection. From these,the utility function F1 derive the instantaneous yield of plateletscontinuously over the processing period.

Yet another utility function F2 relies upon the calculated plateletyield and other processing conditions to generate selected informationalstatus values and parameters. These values and parameters are displayedon the interface 58 to aid the operator in establishing and maintainingoptimal performance conditions. The status values and parameters derivedby the utility function F2 can vary. For example, in the illustratedembodiment, the utility function F2 reports remaining volumes to beprocessed, remaining processing times, and the component collectionvolumes and rates.

Another utility function F3 calculates and recommends, based upon theplatelet yield derived by the utility function F1, the optimal storageparameters for the platelets in terms of the number of storagecontainers and the volume amount of PPP storage media to use.

Other utility functions generate control variables based upon ongoingprocessing conditions for use by the applications control manager 46 toestablish and maintain optimal processing conditions. For example, oneutility function F4 generates control variables to optimize plateletseparation conditions in the first stage 24. Another utility function F5generates control variables to control the rate at which citrateanticoagulant is returned with the PPP to the donor to avoid potentialcitrate toxicity reactions.

Yet another utility function F6 derives an estimated procedure time,which predicts the collection time before the donor is connected.

Further details of these utility functions F1 to F6 will now bedescribed in greater detail.

III. Deriving Platelet Yield

The utility function F1 (see FIG. 4) makes continuous calculations ofthe platelet separation efficiency (η_(Plt)) of the system 10. Theutility function F1 treats the platelet separation efficiency η_(Ptl) asbeing the same as the ratio of plasma volume separated from the donor'swhole blood relative to the total plasma volume available in the wholeblood. The utility function F1 thereby assumes that every platelet inthe plasma volume separated from the donor's whole blood will beharvested.

The donor's hematocrit changes due to anticoagulant dilution and plasmadepletion effects during processing, so the separation efficiencyη_(Plt) does not remain at a constant value, but changes throughout theprocedure. The utility function F1 contends with these process-dependentchanges by monitoring yields incrementally. These yields, calledincremental cleared volumes (ΔClrVol), are calculated by multiplying thecurrent separation efficiency η_(Plt) by the current incremental volumeof donor whole blood, diluted with anticoagulant, being processed, asfollows:

ΔClrVol=ACDil×η_(Plt)×ΔVOL_(Proc)  Eq (1)

where:

ΔVol_(Proc) is the incremental whole blood volume being processed, and

ACDil is an anticoagulant dilution factor for the incremental wholeblood volume, computed as follows: $\begin{matrix}{{A\quad C\quad D\quad i\quad l} = \frac{A\quad C}{{A\quad C} + 1}} & {{Eq}\quad (2)}\end{matrix}$

where:

AC is the selected ratio of whole blood volume to anticoagulant volume(for example 10:1 or “10”). AC may comprise a fixed value during theprocessing period. Alternatively, AC may be varied in a staged fashionaccording to prescribed criteria during the processing period.

For example, AC can be set at the outset of processing at a lesser ratiofor a set initial period of time, and then increased in steps aftersubsequent time periods; for example, AC can be set at 6:1 for the firstminute of processing, then raised to 8:1 for the next 2.5 to 3 minutes;and finally raised to the processing level of 10:1.

The introduction of anticoagulant can also staged by monitoring theinlet pressure of PRP entering the second processing stage 32. Forexample, AC can be set at 6:1 until the initial pressure (e.g. at 500mmHg) falls to a set threshold level (e.g., 200 mmHg to 300 mmHg). ACcan then be raised in steps up to the processing level of 10:1, whilemonitoring the pressure to assure it remains at the desired level.

The utility function F1 also makes continuous estimates of the donor'scurrent circulating platelet count (Plt_(Circ)), expressed in terms of1000 platelets per microliter (μl) of plasma volume (or k/μl). Likeη_(Plt), Plt_(Circ) will change during processing due to the effects ofdilution and depletion. The utility function F1 incrementally monitorsthe platelet yield in increments, too, by multiplying each incrementalcleared plasma volume ΔClrVol (based upon an instantaneous calculationof η_(Plt)) by an instantaneous estimation of the circulating plateletcount Plt_(Cir). The product is an incremental platelet yield (Δyld),typically expressed as e^(n) platelets, where e^(n)=0.5×10^(n) platelets(e¹¹=0.5×10¹¹ platelets).

At any given time, the sum of the incremental platelet yields ΔYldconstitutes the current platelet yield Yld_(Current), which can also beexpressed as follows: $\begin{matrix}{{Yld}_{Current} = {{Yld}_{Old} + \frac{\Delta \quad {ClrVol} \times {Plt}_{Cur}}{100\text{,}000}}} & {{Eq}\quad (3)}\end{matrix}$

where:

Yld_(Old) is the last calculated Yld_(Current), and $\begin{matrix}{{\Delta \quad {Yld}} = \frac{\Delta \quad {ClrVol} \times {Plt}_{Current}}{100\text{,}000}} & {{Eq}\quad (4)}\end{matrix}$

where:

Plt_(Current) is the current (instantaneous) estimate of the circulatingplatelet count of the donor.

ΔYld is divided by 100,000 in Eq (4) to balance units.

The following provides further details in the derivation of theabove-described processing variables by the utility function F1.

A. Deriving Overall Separation Efficiency η_(Plt)

The overall system efficiency η_(Plt) is the product of the individualefficiencies of the parts of the system, as expressed as follows:

η_(plt=η) _(1stSep)×η_(2ndSep)×η_(Anc)  Eq (5)

where:

η_(1stSep) is the efficiency of the separation of PRP from WB in thefirst separation stage.

η_(2ndSep) is the efficiency of separation PC from PRP in the secondseparation stage.

η_(Anc) is the product of the efficiencies of other ancillary processingsteps in the system.

1. First Stage Separation Efficiency η_(1stSep)

The utility function F1 (see FIG. 4) derives η_(1stSep) continuouslyover the course of a procedure based upon measured and empiricalprocessing values, using the following expression: $\begin{matrix}{\eta_{Sep} = \frac{Q_{p}}{\left( {1 - H_{b}} \right)Q_{b}}} & {{Eq}\quad (6)}\end{matrix}$

where:

Q_(b) is the measured whole blood flow rate (in ml/min).

Q_(p) is the measured PRP flow rate (in ml/min).

H_(b) is the apparent hematocrit of the anticoagulated whole bloodentering the first stage separation compartment. H_(b) is a valuederived by the utility based upon sensed flow conditions and theoreticalconsiderations. The utility function F1 therefore requires no on-linehematocrit sensor to measure actual WB hematocrit.

The utility function F1 derives H_(b) based upon the followingrelationship: $\begin{matrix}{H_{b} = \frac{H_{rbc}\left( {Q_{b} - Q_{p}} \right)}{Q_{b}}} & {{Eq}\quad (7)}\end{matrix}$

where:

H_(rbc) is the apparent hematocrit of the RBC bed within the first stageseparation chamber, based upon sensed operating conditions and thephysical dimensions of the first stage separation chamber. As withH_(b), the utility function F1 requires no physical sensor to determineH_(rbc), which is derived by the utility function according to thefollowing expression: $\begin{matrix}{H_{rbc} = {1 - \left( {\frac{\beta}{g\quad A\quad \kappa \quad S_{\mathrm{\Upsilon}}}\left( {q_{b} - q_{p}} \right)} \right)^{\frac{1}{k + 1}}}} & {{Eq}\quad (8)}\end{matrix}$

where:

q_(b) is inlet blood flow rate (cm³/sec), which is a known quantitywhich, when converted to ml/min, corresponds with Q_(b) in Eq (6).

q_(p) is measured PRP flow rate (in cm³/sec), which is a known quantitywhich, when converted to ml/min corresponds with Q_(p) in Eq (6).

β is a shear rate dependent term, and S_(Y) is the red blood cellsedimentation coefficient (sec). Based upon empirical data, Eq (8)assumes that β/S_(Y)=15.8×10⁶ sec⁻¹.

A is the area of the separation chamber (cm²), which is a knowndimension.

g is the centrifugal acceleration (cm/sec²), which is the radius of thefirst separation chamber (a known dimension) multiplied by the rate ofrotation squared Ω² (rad/sec²) (another known quantity).

k is a viscosity constant=0.625, and K is a viscosity constant basedupon k and another viscosity constant α=4.5, where: $\begin{matrix}{\kappa = {{\frac{k + 2}{\alpha}\left\lbrack \frac{k + 2}{k + 1} \right\rbrack}^{k + 1} = 1.272}} & {{Eq}\quad (9)}\end{matrix}$

Eq (8) is derived from the relationships expressed in the following Eq(10): $\begin{matrix}{{H_{rbc}\left( {1 - H_{rbc}} \right)}^{({k + 1})} = \frac{\beta \quad H_{b}q_{b}}{g\quad A\quad \kappa \quad S_{\mathrm{\Upsilon}}}} & {{Eq}\quad (10)}\end{matrix}$

set forth in Brown, The Physics of Continuous Flow Centrifugal CellSeparation, “Artificial Organs” 1989; 13(1):4-20)). Eq (8) solves Eq(10) for H_(rbc).

2. The Second Stage Separation Efficiency η_(2ndSep)

The utility function F1 (see FIG. 4) also derives η_(2ndSep)continuously over the course of a procedure based upon an algorithm,derived from computer modeling, that calculates what fraction oflog-normally distributed platelets will be collected in the secondseparation stage 32 as a function of their size (mean platelet volume,or MPV), the flow rate (Q_(p)), area (A) of the separation stage 32, andcentrifugal acceleration (g, which is the spin radius of the secondstage multiplied by the rate of rotation squared Ω²).

The algorithm can be expressed in terms of a function shown graphicallyin FIG. 8. The graph plots η_(2ndSep) in terms of a single dimensionlessparameter gAS_(p)/Q_(p),

where:

S_(p)=1.8×10⁻⁹MPV^(⅔)(sec),

and

MPV is the mean platelet volume (femtoliters, fl, or cubic microns),which can be measured by conventional techniques from a sample of thedonor's blood collected before processing. There can be variations inMPV due to use of different counters. The utility function therefore mayinclude a look up table to standardize MPV for use by the functionaccording to the type of counter used. Alternatively, MPV can beestimated based upon a function derived from statistical evaluation ofclinical platelet precount Plt_(PRE) data, which the utility functioncan use. The inventor believes, based upon his evaluation of suchclinical data, that the MPV function can be expressed as:

MPV(fl)≈11.5−0.009Plt_(PRE)(k/μl)

3. Ancillary Separation Efficiencies η_(Anc)

η_(Anc) takes into account the efficiency (in terms of platelet loss) ofother portions of the processing system. η_(Anc) takes into account theefficiency of transporting platelets (in PRP) from the first stagechamber to the second stage chamber; the efficiency of transportingplatelets (also in PRP) through the leukocyte removal filter; theefficiency of resuspension and transferral of platelets (in PC) from thesecond stage chamber after processing; and the efficiency ofreprocessing previously processed blood in either a single needle or adouble needle configuration.

The efficiencies of these ancillary process steps can be assessed basedupon clinical data or estimated based upon computer modeling. Based uponthese considerations, a predicted value for η_(Anc) can be assigned,which Eq (5) treats as constant over the course of a given procedure.

B. Deriving Donor Platelet Count (Plt_(Circ))

The utility function F1 (see FIG. 4) relies upon a kinetic model topredict the donor's current circulating platelet count Plt_(Circ) duringprocessing. The model estimates the donor's blood volume, and thenestimates the effects of dilution and depletion during processing, toderive Plt_(Circ), according to the following relationships:

Plt_(Circ)=[(Dilution)×Plt_(pre)]−(Depletion)  Eq (11)

where:

Plt_(pre) is the donor's circulating platelet count before processingbegins (k/μl), which can be measured by conventional techniques from asample of whole blood taken from the donor before processing. There canbe variations in Plt_(pre) due to use of different counters (see, e.g.,Peoples et al., “A Multi-Site Study of Variables Affecting PlateletCounting for Blood Component Quality Control,” Transfusion (SpecialAbstract Supplement, 47th Annual Meeting), v. 34, No. 10S, October 1994Supplement). The utility function therefore may include a look up tableto standardize all platelet counts (such as, Plt_(pre) and Pltpost,described later) for use by the function according to the type ofcounter used.

Dilution is a factor that reduces the donor's preprocessing circulatingplatelet count Plt_(pre) due to increases in the donor's apparentcirculating blood volume caused by the priming volume of the system andthe delivery of anticoagulant. Dilution also takes into account thecontinuous removal of fluid from the vascular space by the kidneysduring the procedure.

Depletion is a factor that takes into account the depletion of thedonor's available circulating platelet pool by processing. Depletionalso takes into account the counter mobilization of the spleen inrestoring platelets into the circulating blood volume during processing.

1. Estimating Dilution

The utility function F1 estimates the dilution factor based upon thefollowing expression: $\begin{matrix}{{Dilution} = {1 - \frac{{Prime} + \frac{2{ACD}}{3} - {PPP}}{DonVol}}} & {{Eq}\quad (12)}\end{matrix}$

where:

Prime is the priming volume of the system (ml).

ACD is the volume of anticoagulant used (current or end-point, dependingupon the time the derivation is made)(ml).

PPP is the volume of PPP collected (current or goal) (ml).

DonVol (ml) is the donor's blood volume based upon models that take intoaccount the donor's height, weight, and sex. These models are furthersimplified using empirical data to plot blood volume against donorweight linearized through regression to the following, more streamlinedexpression:

DonVol=1024+51Wgt(r²=0.87)  Eq (13)

where:

Wgt is the donor's weight (kg).

2. Estimating Depletion

The continuous collection of platelets depletes the availablecirculating platelet pool. A first order model predicts that the donor'splatelet count is reduced by the platelet yield (Yld) (current or goal)divided by the donor's circulating blood volume (DonVol), expressed asfollows: $\begin{matrix}{{Depl} = \frac{100\text{,}000\quad {Yld}}{DonVol}} & {{Eq}\quad (14)}\end{matrix}$

where:

Yld is the current instantaneous or goal platelet yield (k/μl). In Eq(14), Yld is multiplied by 100,000 to balance units.

Eq (14) does not take into account splenic mobilization of replacementplatelets, which is called the splenic mobilization factor (or Spleen).Spleen indicates that donors with low platelets counts nevertheless havea large platelet reserve held in the spleen. During processing, ascirculating platelets are withdrawn from the donor's blood, the spleenreleases platelets it holds in reserve into the blood, thereby partiallyoffsetting the drop in circulating platelets. The inventor hasdiscovered that, even though platelet precounts vary over a wide rangeamong donors, the total available platelet volume remains remarkablyconstant among donors. An average apparent donor volume is 3.10±0.25 mlof platelets per liter of blood. The coefficient of variation is 8.1%,only slightly higher than the coefficient of variation in hematocritseen in normal donors.

The inventor has derived the mobilization factor Spleen from comparingactual measured depletion to Depl (Eq (14)), which is plotted andlinearized as a function of Plt_(Pre). Spleen (which is restricted to alower limit of 1) is set forth as follows:

Spleen=[2.25−0.004Plt_(Pre)]≧1  Eq (15)

Based upon Eqs (14) and (15), the utility function derives Depletion asfollows: $\begin{matrix}{{Depletion} = \frac{100\text{,}000\quad {Yld}}{{Spleen} \times {DonVol}}} & {{Eq}\quad (16)}\end{matrix}$

C. Real Time Procedure Modifications

The operator will not always have a current platelet pre-count Plt_(Pre)for every donor at the beginning of the procedure. The utility functionF1 allows the system to launch under default parameters, or values froma previous procedure. The utility function F1 allows the actual plateletpre-count Plt_(Pre), to be entered by the operator later during theprocedure. The utility function F1 recalculates platelet yieldsdetermined under one set of conditions to reflect the newly enteredvalues. The utility function F1 uses the current yield to calculate aneffective cleared volume and then uses that volume to calculate the newcurrent yield, preserving the platelet pre-count dependent nature ofsplenic mobilization.

The utility function F1 uses the current yield to calculate an effectivecleared volume as follows:

$\begin{matrix}{{lrVol} = \frac{100\text{,}000\quad \times {DonVol} \times {Yld}_{Current}}{{\left\lbrack {{DonVol} - {Prime} - \frac{ACD}{3} + \frac{PPP}{2}} \right\rbrack \times {Pre}_{Old}} - \frac{50\text{,}000 \times {Yld}_{current}}{{Spleen}_{Old}}}} & {{Eq}\quad (17)}\end{matrix}$

where:

ClrVol is the cleared plasma volume.

DonVol is the donor's circulating blood volume, calculated according toEq (13).

Yld_(Current) is the current platelet yield calculated according to Eq(3) based upon current processing conditions.

Prime is the blood-side priming volume (ml).

ACD is the volume of anticoagulant used (ml).

PPP is the volume of platelet-poor plasma collected (ml).

Pre_(Old) is the donor's platelet count before processing entered beforeprocessing begun (k/μl).

Spleen_(Old) is the splenic mobilization factor calculated using Eq (16)based upon Pre_(Old).

The utility function F1 uses ClrVol calculated using Eq (17) tocalculate the new current yield as follows: $\begin{matrix}{{Yld}_{New} = {\left\lbrack \frac{{DonVol} - {Prime} - \frac{ACD}{3} + \frac{PPP}{2}}{{DonVol} + \frac{ClrVol}{2 \times {Spleen}_{New}}} \right\rbrack \times \left\lbrack \frac{{ClrVol} \times {Pre}_{New}}{100\text{,}000} \right\rbrack}} & {{Eq}\quad (18)}\end{matrix}$

where:

Pre_(New) is the revised donor platelet pre-count entered duringprocessing (k/μl).

Yld_(New) is the new platelet yield that takes into account the reviseddonor platelet pre-count Pre_(New).

ClrVol is the cleared plasma volume, calculated according to Eq (17).

DonVol is the donor's circulating blood volume, calculated according toEq (13), same as in Eq (17).

Prime is the blood-side priming volume (ml), same as in Eq (17).

ACD is the volume of anticoagulant used (ml), same as in Eq (17).

PPP is the volume of platelet-poor plasma collected (ml), same as in Eq(17).

Spleen_(New) is the splenic mobilization factor calculated using Eq (15)based upon Pre_(New).

IV. Deriving Other Processing Information

The utility function F2 (see FIG. 5) relies upon the calculation of Yldby the first utility function F1 to derive other informational valuesand parameters to aid the operator in determining the optimum operatingconditions for the procedure. The follow processing values exemplifyderivations that the utility function F2 can provide.

A. Remaining Volume to be Processed

The utility function F2 calculates the additional processed volumeneeded to achieve a desired platelet yield Vb_(rem) (in ml) by dividingthe remaining yield to be collected by the expected average plateletcount over the remainder of the procedure, with corrections to reflectthe current operating efficiency η_(Plt). The utility function F2derives this value using the following expression: $\begin{matrix}{{Vb}_{r\quad {em}} = \frac{200\text{,}000 \times \left( {{Yld}_{Goal} - {Yld}_{Current}} \right)}{\eta_{Plt} \times {ACDil} \times \left( {{Plt}_{Current} + {Plt}_{Post}} \right)}} & {{Eq}\quad (19)}\end{matrix}$

where:

Yld_(goal) is the desired platelet yield (k/μl), where:

Vb_(rem) is the additional processing volume (ml) needed to achieveYld_(Goal).

Yld_(Current) is the current platelet yield (k/μl), calculated using Eq(3) based upon current processing values.

η_(Plt) is the present (instantaneous) platelet collection efficiency,calculated using Eq (5) based upon current processing values.

ACDil is the anticoagulant dilution factor (Eq (2)).

Plt_(current) is the current (instantaneous) circulating donor plateletcount, calculated using Eq (11) based upon current processing values.

Plt_(Post) is the expected donor platelet count after processing, alsocalculated using Eq (11) based upon total processing values.

B. Remaining Procedure Time

The utility function F2 also calculates remaining collection time(t_(rem)) (in min) as follows: $\begin{matrix}{t_{r\quad {em}} = \frac{{Vb}_{r\quad {em}}}{Q_{b}}} & {{Eq}\quad (20)}\end{matrix}$

where:

Vb_(rem) is the remaining volume to be processed, calculated using Eq(19) based upon current processing conditions.

Q^(b) is the whole blood flow rate, which is either set by the user orcalculated as Q^(b) _(Opt) using Eq (31), as will be described later.

C. Plasma Collection

The utility function F2 adds the various plasma collection requirementsto derive the plasma collection volume (PPP_(Goal)) (in ml) as follows:

PPP_(Goal)=PPP_(PC)+PPP_(Source)+PPP_(Reinfuse)+PPP_(Waste)+PPP_(CollCham)  Eq(21)

where:

PPP_(PC) is the platelet-poor plasma volume selected for the PC product,which can have a typical default value of 250 ml, or be calculated as anoptimal value Plt_(Med) according to Eq (28), as will be describedlater.

PPP_(Source) is the platelet-poor plasma volume selected for collectionas source plasma.

PPP_(Waste) is the platelet-poor plasma volume selected to be held inreserve for various processing purposes (Default=30 ml).

PPP_(CollCham) is the volume of the plasma collection chamber(Default=40 ml).

PPP_(Reinfuse) is the platelet-poor plasma volume that will bereinfusion during processing.

D. Plasma Collection Rate

The utility function F2 calculates the plasma collection rate (Q_(ppp))(in ml/min) as follows: $\begin{matrix}{Q_{PPP} = \frac{{PPP}_{Goal} - {PPP}_{Current}}{t_{r\quad {em}}}} & {{Eq}\quad (22)}\end{matrix}$

where:

PPP_(Goal) is the desired platelet-poor plasma collection volume (ml).

PPP_(Current) is the current volume of platelet-poor plasma collected(ml).

t_(rem) is the time remaining in collection, calculated using Eq (20)based upon current processing conditions.

E. Total Anticipated AC Usage

The utility function F2 can also calculate the total volume ofanticoagulant expected to be used during processing (ACD_(End)) (in ml)as follows: $\begin{matrix}{{ACD}_{End} = {{ACD}_{Current} + \frac{Q_{b} \times t_{r\quad {em}}}{1 + {A\quad C}}}} & {{Eq}\quad (23)}\end{matrix}$

where:

ACD_(Current) is the current volume of anticoagulant used (ml).

AC is the selected anticoagulant ratio,

Q_(b) is the whole blood flow rate, which is either set by the user orcalculated using Eq (31) as Q^(b) _(Opt) based upon current processingconditions.

t_(rem) is the time remaining in collection, calculated using Eq (20)based upon current processing conditions.

V. Recommending optimum Platelet Storage Parameters

The utility function F3 (see FIG. 6) relies upon the calculation of Yldby the utility function F1 to aid the operator in determining theoptimum storage conditions for the platelets collected duringprocessing.

The utility function F3 derives the optimum storage conditions tosustain the platelets during the expected storage period in terms of thenumber of preselected storage containers required for the plateletsPlt_(Bag) and the volume of plasma (PPP) Plt_(Med) (in ml) to reside asa storage medium with the platelets.

The optimal storage conditions for platelets depends upon the volumebeing stored Plt_(Vol), expressed as follows:

Plt_(Vol)=Yld×MPV  Eq (24)

where:

Yld is the number of platelets collected, and

MPV is the mean platelet volume.

As Plt_(Vol) increases, so too does the platelets' demand for oxygenduring the storage period. As Plt_(Vol) increases, the platelets'glucose consumption to support metabolism and the generation of carbondioxide and lactate as a result of metabolism also increase. Thephysical characteristics of the storage containers in terms of surfacearea, thickness, and material are selected to provide a desired degreeof gas permeability to allow oxygen to enter and carbon dioxide toescape the container during the storage period.

The plasma storage medium contains bicarbonate HCO₃, which buffers thelactate generated by platelet metabolism, keeping the pH at a level tosustain platelet viability. As Plt_(Vol) increases, the demand for thebuffer effect of HCO₃, and thus more plasma volume during storage, alsoincreases.

A. Deriving Plt_(Bag)

The partial pressure of oxygen pO₂ (mmHg) of platelets stored within astorage container having a given permeation decreases in relation to thetotal platelet volume Plt_(Vol) the container holds. FIG. 9 is a graphbased upon test data showing the relationship between pO₂ measured afterone day of storage for a storage container of given permeation. Thestorage container upon which FIG. 9 is based has a surface area of54.458 in² and a capacity of 1000 ml. The storage container has apermeability to O₂ of 194 cc/100 in²/day, and a permeability to CO₂ 1282cc/100 in²/day.

When the partial pressure pO₂ drops below 20 mmHg, platelets areobserved to become anaerobic, and the volume of lactate byproductincreases significantly. FIG. 9 shows that the selected storagecontainer can maintain pO₂ of 40 mmHg (well above the aerobic region) atPlt_(Vol)≦4.0 ml. On this conservative basis, the 4.0 ml volume isselected as the target volume Plt_(TVol) for this container. Targetvolumes Plt_(TVol) for other containers can be determined using thissame methodology.

The utility function F3 uses the target platelet volume Plt_(TVol) tocompute Plt_(Bag) as follows: $\begin{matrix}{{BAG} = \frac{{Plt}_{Vol}}{{Plt}_{TVol}}} & {{Eq}\quad (25)}\end{matrix}$

and:

Plt_(Bag)=1 when BAG≦1.0, otherwise

Plt_(Bag)=[BAG+1], where [BAG+1] is the integer part of the quantityBAG+1.

For example, given a donor MPV of 9.5 fl, and a Yld of 4×10¹¹ platelets(Plt_(Vol)=3.8 ml), and given Plt_(TVol)=4.0 ml, BAG=0.95, andPlt_(Bag)=1. If the donor MPV is 11.0 fl and the yield Yld andPlt_(TVol) remain the same (Plt_(Vol)=4.4 ml), BAG=1.1 and Plt_(Bag)=2.

When Plt_(Bag)>1, Plt_(Vol) is divided equally among the number ofcontainers called for.

B. Deriving Plt_(Med)

The amount of bicarbonate used each day is a function of the storagethrombocytocrit Tct (%), which can be expressed as follows:$\begin{matrix}{{Tct} = \frac{{Plt}_{Vol}}{{Plt}_{Med}}} & {{Eq}\quad (26)}\end{matrix}$

The relationship between bicarbonate HCO₃ consumption per day and Tctcan be empirically determined for the selected storage container. FIG.10 shows a graph showing this relationship for the same container thatthe graph in FIG. 9 is based upon. The y-axis in FIG. 10 shows theempirically measured consumption of bicarbonate per day (in Meq/L) basedupon Tct for that container. The utility function F3 includes the dataexpressed in FIG. 10 in a look-up table.

The utility function F3 derives the anticipated decay of bicarbonate perday over the storage period ΔHCO₃ as follows: $\begin{matrix}{{\Delta \quad {HCO}_{3}} = \frac{{Don}_{{HCO}_{3}}}{Stor}} & {{Eq}\quad (27)}\end{matrix}$

where:

Don_(HCO3) is the measured bicarbonate level in the donor's blood(Meq/L), or alternatively, is the bicarbonate level for a typical donor,which is believed to be 19.0 Meq/L±1.3, and

Stor is the desired storage interval (in days, typically between 3 to 6days).

Given ΔHCO₃, the utility function F3 derives Tct from the look up tablefor selected storage container. For the storage container upon whichFIG. 10 is based, a Tct of about 1.35 to 1.5% is believed to beconservatively appropriate in most instances for a six day storageinterval.

Knowing Tct and Plt_(Vol), the utility function F3 computes Plt_(Med)based upon Eq (25), as follows: $\begin{matrix}{{Plt}_{Med} = \frac{{Plt}_{Vol}}{\frac{Tct}{100}}} & {{Eq}\quad (28)}\end{matrix}$

When Plt_(Bag)>1, Plt_(Med) is divided equally among the number ofcontainers called for. PPP_(PC) is set to Plt_(Med) in Eq (21).

VI. Deriving Control Variables

The utility functions F4 and F5 rely upon the above-described matrix ofphysical and physiological relationships to derive process controlvariables, which the application control manager 46 uses to optimizesystem performance. The follow control variables exemplify derivationsthat the utility functions F4 and F5 can provide for this purpose.

A. Promoting High Platelet Separation Efficiencies By Recirculation

A high mean platelet value MPV for collected platelets is desirable, asit denotes a high separation efficiency for the first separation stageand the system overall. Most platelets average about 8 to 10femtoliters, as measured by the Sysmex K-1000 machine (the smallest ofred blood cells begin at about 30 femtoliters). The remaining minorityof the platelet population constitutes platelets that are physicallylarger. These larger platelets typically occupy over 15×10⁻¹⁵ liter perplatelet, and some are larger than 30 femtoliters.

These larger platelets settle upon the RBC interface in the firstseparation chamber quicker than most platelets. These larger plateletsare most likely to become entrapped in the RBC interface and not enterthe PRP for collection. Efficient separation of platelets in the firstseparation chamber lifts the larger platelets from the interface forcollection in the PRP. This, in turn, results a greater population oflarger platelets in the PRP, and therefore a higher MPV.

FIG. 11, derived from clinical data, shows that the efficiency ofplatelet separation, expressed in terms of MPV, is highly dependent uponthe inlet hematocrit of WB entering the first stage processing chamber.This is especially true at hematocrits of 30% and below, wheresignificant increases in separation efficiencies can be obtained.

Based upon this consideration, the utility function F4 sets a rate forrecirculating PRP back to the inlet of the first separation stageQ_(Recirc) to achieve a desired inlet hematocrit H_(i) selected toachieve a high MPV. The utility function F4 selects H_(i) based upon thefollowing red cell balance equation: $\begin{matrix}{Q_{Recirc} = {\left\lbrack {\frac{H_{b}}{H_{i}} - 1} \right\rbrack \times Q_{b}}} & {{Eq}\quad (29)}\end{matrix}$

In a preferred implementation, H_(i) is no greater that about 40%, and,most preferably, is about 32%.

B. Citrate Infusion Rate

Citrate in the anticoagulant is rapidly metabolized by the body, thusallowing its continuous infusion in returned PPP during processing.However, at some level of citrate infusion, donors will experiencecitrate toxicity. These reactions vary in both strength and nature, anddifferent donors have different threshold levels. A nominala-symptomatic citrate infusion rate (CIR), based upon empirical data, isbelieved to about 1.25 mg/kg/min. This is based upon empirical data thatshows virtually all donors can tolerate apheresis comfortably at ananticoagulated blood flow rates of 45 ml/min with an anticoagulant(ACD-A anticoagulant) ratio of 10:1.

Taking into account that citrate does not enter the red cells, theamount given to the donor can be reduced by continuously collecting somefraction of the plasma throughout the procedure, which the systemaccomplishes. By doing so, the donor can be run at a higher flow ratethan would be expected otherwise. The maximum a-symptomatic equivalentblood flow rate (EqQ^(b) _(CIR)) (in ml/min) under these conditions isbelieved to be: $\begin{matrix}{{EqQb}_{CIR} = \frac{{CIR} \times \left( {{A\quad C} + 1} \right) \times {Wgt}}{{Citrate}\quad {Conc}}} & {{Eq}\quad (30)}\end{matrix}$

where:

CIR is the selected nominal a-symptomatic citrate infusion rate, or 1.25mg/kg/min.

AC is the selected anticoagulant ratio, or 10:1.

Wgt is the donor's weight (kg).

CitrateConc is the citrate concentration in the selected anticoagulant,which is 21.4 mg/ml for ACD-A anticoagulant.

C. Optimum Anticoagulated Blood Flow

The remaining volume of plasma that will be returned to the donor isequal to the total amount available reduced by the amount still to becollected. This ratio is used by the utility function F5 (see FIG. 5) todetermine the maximum, or optimum, a-symptomatic blood flow rate (Q^(b)_(Opt)) (in ml/min) that can be drawn from the donor, as follows:$\begin{matrix}{{Qb}_{Opt} = {\frac{\left( {1 - H_{b}} \right) \times {Vb}_{r\quad {em}}}{{\left( {1 - H_{b}} \right) \times {Vb}_{r\quad {em}}} - \left( {{PPP}_{Goal} - {PPP}_{Current}} \right)} \times {EqQb}_{CIR}}} & {{Eq}\quad (31)}\end{matrix}$

where:

H_(b) is the anticoagulated hematocrit, calculated using Eq (7) basedupon current processing conditions.

Vb_(Rem) is the remaining volume to be processed, calculated using Eq(19) based upon current processing conditions.

EqQ^(B) _(CIR) is the citrate equivalent blood flow rate, calculatedusing Eq (30) based upon current processing conditions.

PPP_(Goal) is the total plasma volume to be collected (ml).

PPP_(Current) is the current plasma volume collected (ml).

VII. Estimated Procedure Time

The utility function F6 (see FIG. 7) derives an estimated procedure time(t) (in min), which predicts the collection time before the donor isconnected. To derive the estimated procedure time t, the utilityfunction F6 requires the operator to input the desired yield Yld_(Goal)and desired plasma collection volume PPP_(Goal), and further requiresthe donor weight Wgt, platelet pre-count Plt_(Pre), and hematocrit H_(b)or a default estimate of it. If the operator wants recommended plateletstorage parameters, the utility function requires MPV as an input.

The utility function F6 derives the estimated procedure time t asfollows: $\begin{matrix}{t = \frac{{- b} + \sqrt{b^{2} - {4a\quad c}}}{2a}} & {{Eq}\quad (32)}\end{matrix}$

where: $\begin{matrix}{a = {\frac{H_{eq} - H_{b}}{\left( {1 - H_{b}} \right)}{EqQb}_{CIR}}} & {{Eq}\quad (33)}\end{matrix}$

$\begin{matrix}{b = {\frac{\left( {H_{eq} - H_{b} - {\lambda \quad H_{b}{EqQb}_{CIR}}} \right){PPP}}{\left( {1 - H_{b}} \right)^{2}} - {H_{Eq}{PV}}}} & {{Eq}\quad (34)}\end{matrix}$

$\begin{matrix}{c = {\left\lbrack {{PV} - \frac{PPP}{\left( {1 - H_{b}} \right)^{2}}} \right\rbrack \lambda \quad H_{b}\frac{PPP}{\left( {1 - H_{b}} \right)}}} & {{Eq}\quad (35)}\end{matrix}$

and where:

H_(eq) is a linearized expression of the RBC hematocrit H_(RBC), asfollows:

H_(eq)=0.9489−λH_(b)EqQ^(b) _(CIR)  Eq (36)

where:

H_(b) is the donor's anticoagulated hematocrit, actual or defaultestimation.

EqQ^(b) _(CIR) is the maximum a-symptomatic equivalent blood flow ratecalculated according to Eq (30).

and $\begin{matrix}{\lambda = \frac{61\text{,}463}{\Omega^{2}}} & {{Eq}\quad (37)}\end{matrix}$

where:

Ω is the rotation speed of the processing chamber (rpm).

and where:

PPP is the desired volume of plasma to be collected (ml).

PV is the partial processed volume, which is that volume that would needto be processed if the overall separation efficiency η_(Plt) was 100%,derived as follows: $\begin{matrix}{{PV} = \frac{ClrVol}{\eta_{Anc} \times \eta_{2{ndSep}} \times {ACDil}}} & {{Eq}\quad (38)}\end{matrix}$

where:

ACDil is the anticoagulant dilution factor (Eq (2)).

ClrVol is the cleared volume, derived as: $\begin{matrix}{{ClrVol} = \frac{100\text{,}000 \times {DonVol} \times {Yld}}{{\left\lbrack {{DonVol} - {Prime} - \frac{{ACD}_{Est}}{3} + \frac{PPP}{2}} \right\rbrack \times {Plt}_{Pre}} - \frac{50\text{,}000 \times {Yld}}{Spleen}}} & {{Eq}\quad (39)}\end{matrix}$

where:

Yld is the desired platelet yield.

DonVol is the donor's blood volume=1024+51Wgt (ml).

Prime is the blood side priming volume of the system (ml).

ACD_(Est) is the estimated anticoagulant volume to be used (ml).

Plt_(Pre) is the donor's platelet count before processing, or a defaultestimation of it.

Spleen is the is the splenic mobilization factor calculated using Eq(16) based upon Plt_(Pre).

The function F6 also derives the volume of whole blood needed to beprocessed to obtain the desired Yld_(Goal). This processing volume,WBVol, is expressed as follows:${WBVol} = {{t \times {EqQb}_{CIR} \times \frac{{PPP}_{Goal}}{\left( {1 - H_{b}} \right)}} + {WB}_{RES}}$

where:

t is the estimated procedure time derived according to Eq(32).

H_(b) is the donor's anticoagulated hematocrit, actual or defaultestimation.

EqQ^(b) _(CIR) is the maximum a-symptomatic equivalent blood flow ratecalculated according to Eq (30).

PPP_(GOAL) is the desired plasma collection volume.

WB_(RES) is the residual volume of whole blood left in the system afterprocessing, which is a known system variable and depends upon thepriming volume of the system.

Various features of the inventions are set forth in the followingclaims.

I claim:
 1. A blood processing system comprising a centrifugalseparation device rotatable about a rotational axis at a controlled rateof rotation, the separation device having an area A, an inlet pathoperable to convey whole blood at a determinable rate Q_(b) into theseparation device for separation into red blood cells and a plasmaconstituent, the whole blood in the inlet path having an actual wholeblood hematocrit value, the red blood cells in the separation devicehaving an actual red blood cell hematocrit value, an outlet pathoperable to remove plasma constituent from the separation device at adeterminable rate Q_(p) at least in part while whole blood is conveyedinto the separation device, an outlet path operable to remove red bloodcells from the separation device at least in part while whole blood isconveyed into the separation device and plasma is removed from theseparation device, a controller including a stage operable, at least inpart while whole blood is conveyed into the separation device and plasmaand red blood cells are removed from the separation device, to derive avalue H_(b) representing an apparent hematocrit of whole blood enteringthe separation device and a value H_(rbc) representing an apparenthematocrit of red blood cells within the separation device, where:H_(b)=f(H_(rbc)) and where: H_(rbc)=f(Q_(b), Q_(p), A, g, RBC) where: grepresents a centrifugal acceleration factor based upon the controlledrate of rotation, and RBC represents at least one red blood celldependent factor not including either the actual whole blood hematocritvalue or the actual red blood cell hematocrit value, and the controllerincluding a stage operable to generate a control command at least inpart while whole blood is conveyed into the separation device and plasmaand red blood cells are removed from the separation device, based, atleast in part, upon H_(b).
 2. A system according to claim 1 wherein, thecontroller derives H_(b) based upon a relationship among H_(rbc), Q_(b),Q_(p), and not including the actual whole blood hematocrit value,expressed as follows:$H_{b} = \frac{H_{rbc}\left( {Q_{b} - Q_{p}} \right)}{Q_{b}}$


3. A system according to claim 1 wherein the control commandrecirculates at least a portion of plasma constituent for mixing withwhole blood conveyed into the separation device.
 4. A system accordingto claim 3 wherein the control command recirculates at least a portionof plasma constituent at a rate Q_(Recirc) to achieve a desiredhematocrit H_(i) for whole blood conveyed into the separation device. 5.A system according to claim 4 wherein Q_(Recirc) is derived as follows:$Q_{Recirc} = {\left\lbrack {\frac{H_{b}}{H_{i}} - 1} \right\rbrack \times {Q_{b}.}}$


6. A system according to claim 4 wherein H_(i) is no greater than about40%.
 7. A system according to claim 4 wherein H_(i) is about 32%.
 8. Asystem according to claim 1 wherein the control command controls H_(b).9. A system according to claim 1 and further including an element thatgenerates an output based, at least in part, upon H_(b).
 10. A systemaccording to claim 9 wherein the output comprises a value η representingefficiency of separation in the separation device, where:$\eta = \frac{Q_{p}}{\left( {1 - H_{b}} \right)Q_{b}}$


11. A system according to claim 1 wherein the controller derives H_(rbc)according to the following relationship:$H_{rbc} = {1 - \left( {\frac{\beta}{g\quad A\quad \kappa \quad S_{\mathrm{\Upsilon}}}\left( {q_{b} - q_{p}} \right)} \right)^{\frac{1}{k + 1}}}$

where: Q_(b) is inlet blood flow rate (cm³/sec), which when converted toml/min, corresponds with Q_(b), Q_(p) is measured plasma flow rate (incm³/sec), which, when converted to ml/min corresponds with Q_(p), β is ashear rate dependent term, and S_(y) is a red blood cell sedimentationcoefficient (sec) and β/S_(y)=15.8×10⁶ sec⁻¹, A is the area of theseparation device (cm²), g is the centrifugal acceleration (cm/sec²),which is the radius of the separation device multiplied by the rate ofrotation squared Ω² (rad/sec²), and k is a viscosity constant=0.625, andK is a viscosity constant based upon k and another viscosity constantα=4.5, where:$\kappa = {{\frac{k + 2}{\alpha}\left\lbrack \frac{k + 2}{k + 1} \right\rbrack}^{k + 1} = {1.272.}}$


12. A system according to claim 11 wherein the separation device is freeof any sensor operable to measure the actual whole blood hematocritvalue.
 13. A system according to claim 1 wherein the inlet path is freeof any sensor operable to measure the actual whole blood hematocritvalue.
 14. A blood processing method comprising the steps of rotating acentrifugal separation device at a controlled rate of rotation, theseparation device having an area A, conveying whole blood having anactual whole blood hematocrit value into the separation device at adeterminable rate Q_(b) for separation into red blood cells and a plasmaconstituent, the red blood cells in the separation device having anactual red blood cell hematocrit value, removing plasma constituent fromthe separation device at a determinable rate Q_(p) at least in partwhile whole blood is conveyed into the separation device, removing redblood cells from the separation device at least in part while wholeblood is conveyed into the separation device and plasma is removed fromthe separation device, deriving at least in part while whole blood isconveyed into the separation device and plasma and red blood cells areremoved from the separation device a value H_(b) representing anapparent hematocrit of whole blood entering the separation device and avalue H_(rbc) representing an apparent hematocrit of red blood cellswithin the separation device, where: H_(b)=f(H_(rbc)) and where:H_(rbc)=f(Q_(b), Q_(p), A, g, RBC) where: g represents a centrifugalacceleration factor based upon the controlled rate of rotation, and RBCrepresents at least one red blood cell dependent factor not includingeither the actual whole blood hematocrit value or the actual red bloodcell hematocrit value, and generating a control command based, at leastin part, upon H_(b) at least in part while whole blood is conveyed intothe separation device and plasma and red blood cells are removed fromthe separation device.
 15. A method according to claim 14 wherein H_(b)is derived based upon a relationship among H_(rbc), Q_(b), Q_(p), andnot including the actual whole blood hematocrit value, expressed asfollows: $H_{b} = \frac{H_{rbc}\left( {Q_{b} - Q_{p}} \right)}{Q_{b}}$


16. A method according to claim 14 wherein the control commandrecirculates at least a portion of plasma constituent for mixing withwhole blood conveyed into the separation device.
 17. A method accordingto claim 16 wherein the control command recirculates at least a portionof plasma constituent at a rate Q_(Recirc) to achieve a desiredhematocrit H_(i) for whole blood conveyed into the separation device.18. A method according to claim 17 wherein Q_(Recirc) is derived asfollows:$Q_{Recirc} = {\left\lbrack {\frac{H_{b}}{H_{i}} - 1} \right\rbrack \times {Q_{b}.}}$


19. A method according to claim 17 wherein H_(i) is no greater thanabout 40%.
 20. A method according to claim 17 wherein H_(i) is about32%.
 21. A method according to claim 14 wherein the control commandcontrols Q_(b).
 22. A method according to claim 14 and further the stepof generating an output based, at least in part, upon H_(b).
 23. Amethod according to claim 22 wherein the output comprises a value ηrepresenting efficiency of separation in the separation device.
 24. Amethod according to claim 14 wherein the value H_(rbc) is derived asfollows:$H_{rbc} = {1 - \left( {\frac{\beta}{g\quad A\quad \kappa \quad S_{\mathrm{\Upsilon}}}\left( {q_{b} - q_{p}} \right)} \right)^{\frac{1}{k + 1}}}$

where: q_(b) is inlet blood flow rate (cm³/sec), which when converted toml/min, corresponds with Q_(b), q_(p) is measured plasma flow rate (incm³/sec), which, when converted to ml/min corresponds with Q_(p), β is ashear rate dependent term, and S_(y) is a red blood cell sedimentationcoefficient (sec) and β/S_(y)=15.8×10⁶ sec⁻¹, A is the area of theseparation device (cm²), g is the centrifugal acceleration (cm/sec²),which is the radius of the separation device multiplied by the rate ofrotation squared Ω² (rad/sec²), and k is a viscosity constant=0.625, andK is a viscosity constant based upon k and another viscosity constantα=4.5, where:$\kappa = {{\frac{k + 2}{\alpha}\left\lbrack \frac{k + 2}{k + 1} \right\rbrack}^{k + 1} = {1.272.}}$


25. A method according to claim 24 wherein the method is free of a stepof using a sensor to measure the actual whole blood hematocrit value inthe separation device.
 26. A method according to claim 14 wherein themethod is free of a step of using a sensor to measure the actual wholeblood hematocrit value of blood conveyed into the separation device.